Synaptic contacts permit interneuronal communication. Recent studies suggest that synaptic integrity and efficiency are the key elements in maintaining behavioral capacity into old age and that deterioration of synaptic integrity underlies the impairments associated with age-related neurodegenerative diseases. A diminished capacity of the aged brain to remodel synaptic circuitry is a consistent observation and might be responsible for functional changes with aging and the progression of cognitive deterioration in age-associated neurodegenerative diseases. The cause of this diminished synaptic plasticity with aging is unclear. Recent results suggests that the interaction of synaptic membrane proteins with matrix proteins may play an important role. The recent development of transgenic technology in mice has greatly advanced the field to answer such mechanistic questions. To this end, we are developing an unbiased stereology technique to quantify synaptic and neuronal changes in the mouse brain with aging. In terms of molecular mechanisms, we focus on extracellular matrix and synaptic proteins, such as laminins, dystrophin-dystroglycan and amyloid precursor protein (APP). In light of this great potential of inbred and genetically-modified murine models for the neurobiology of aging, our research program is focusing increasingly on the aging mouse brain.